がん増悪因子とその制御に作用する制がん物質の研究

• 研究課題/領域番号: 06282122
• 研究種目: 重点領域研究
• 配分区分: 補助金
• 研究機関: 国立予防衛生研究所
• 研究代表者: 上原 至雅 国立予防衛生研究所, 生物活性物質部, 室長 (50160213)
• 研究分担者: 井本 正哉 慶応義塾大学, 理工学部, 助教授 (60213253) ; 岡田 信子 国立がんセンター研究所, 主任研究官 (70194363) ; 小河原 宏 明治薬科大学, 教授 (00097198) ; 岡部 實裕 北海道大学, 医学部・附属病院, 助手 (40113534) ; 沖 俊一 富山県立大学, 工学部, 教授 (40264676) ; 済木 育夫 富山医薬大, 和漢薬研, 教授 (80133776) ; 小宮山 寛機 北里研究所, 基礎研, 副所長 (00106676)
• 研究期間 (年度): 1995
• 研究課題ステータス: 完了 (1995年度)
• 配分額: 47,300千円 (直接経費: 47,300千円); 1995年度: 24,000千円 (直接経費: 24,000千円); 1994年度: 23,300千円 (直接経費: 23,300千円)
• キーワード: がん遺伝子 / シグナル伝達 / 制がん物質 / がん抑制遺伝子 / IL-6 / 転移 / 血管新生 / 薬剤耐性 / 制がん剤

研究概要

1.非接着性ポリマーを用いた足場非依存増殖の定量をヒト上皮由来のがん細胞でも検討し、がん化シグナル抑制物質探索への有用性を示した。
2.がん化シグナルに作用する物質の探索から得たエンジェルマイシンの化学構造を決定し、アザチロシンの分子標的を解析した。
3.CMLの進展にDNAメチル化の異常が高頻度にみられること、活性なPI3-kinaseに結合する蛋白質リン酸化酵素の存在を示した。
4.細胞周期においてサイクリンD1の過剰発現がG1期を短縮させる機構と、RB欠損のがん細胞を選択的にアポトーシス誘導する新規化合物の作用を解析した。
5.IL-6の活性修飾物質の探索から新規化合物を見いだし、悪液質抑制効果を観察した。また、IL-6刺激により、Stat3がCRE類似部位結合性36kDa分子と複合体を形成することを見いだした。
6.RGDS誘導体の中に転移を抑制する化合物を見いだしその分子機構を解析し、リゾキシンの血管新生阻害作用が血管内皮機能の抑制によることを示した。
7.ヒト結腸がん5-FU耐性細胞の耐性機構を解析し、薬剤接触時間の違いが感受性を変化させること、また、多剤耐性がん細胞へM-CSF遺伝子を導入することで転移抑制効果が得られることを示した。

研究成果

• [文献書誌] Fukazawa, H.: "A microplate assay for quantitation of anchorage-independent growth of transformed cells." Anal. Biochem.228. 83-90 (1995)
• [文献書誌] Hori, H.: "Structure of angelmicin B ; a novel src signal transduction inhibitor." Tettrahedron Lett.(in press).
• [文献書誌] Yokoyama, K.: "Angelmicin B, a new inhibitor of oncogenic signal transduction, inhibits growth and induces of myelomonocytic differentiation of human myeloid leukemia HL-60 cells." Leukemia Res.(in press).
• [文献書誌] Okabe, M.: "Establishment and characterization of a new Ph1-positive chronic myeloid leukemia cell line MC3 with trilineage phenotype and altered p53 gene." Leukemia and Lymphoma. 16. 493-505 (1995)
• [文献書誌] Kunieda, Y.: "Effects of rhG-CSF on infection complication and impaired function of neutrophils secondary to chemotherapy for non-Hodgkin's lymphoma." Leukemia and Lymphoma. 16. 471-476 (1995)
• [文献書誌] Okabe, M.: "Administration of rhG-CSF increases complete remission rates after CHOP and ProMACE/CytaBOM for non-Hodgkin's lymphoma : a pilot study." Leukemia and Lymphoma. 19. 485-491 (1995)
• [文献書誌] Kurosawa, M.: "Analysis of p53 gene mutation in acute myelogenous leukemia : the p53 gene mutations associated with a deletion of chromosome 17." Ann. Hematol.71. 83-87 (1995)
• [文献書誌] Okabe, M.: "Reversal effect of itraconazol on adriamycin- and etoposide-resistance in human leukemia cells." Ann. Hematol.(in press).
• [文献書誌] Okabe, M.: "Megakaryocytic differentiation of leukemic cell line, MC3, by phorbol ester : Induction of glycoprotein IIb/IIIa and effects on expression of IL-6, IL-6 receptor, mpl and GATA genes." Leukemia Res.(in press).
• [文献書誌] Machida, T.: "Cochlioquinone A, an inhibitor of diacylglycerol kinase." J. Antibiotics. 48. 1076-1080 (1995)
• [文献書誌] Monden, Y.: "Stimulation of the expression of rhoB contributes to the ability of azatyrosine to convert c-erbB-2-transformed cells to a normal morphology." Oncogene Reports. 3. 49-55 (1996)
• [文献書誌] Monden, Y.: "Azatyrosine inhibits the activation of c-raf-1, c-jun and AP-1 but not the activation of ras during signal transduction triggered by oncogenic c-erb-2." Oncogene Reports. 3. 33-44 (1996)
• [文献書誌] Mizutani, Y.: "Induction of erythroid differentiation in leukemic K562 cells by an S-adenosylhomocysteine hydrolase inhibitor, aristeromycin." Biochem. Biophys. Res. Commun.207. 69-74 (1995)
• [文献書誌] Ui, H.: "Inhibition of phosphatidylinositol-specific phospholipase C activity by fluvirucin B2." J. Antibiotics. 48. 387-390 (1995)
• [文献書誌] Imoto, M.: "In situ inhibition of protein-tyrosine phosphatase by dephostatin." Cell. Pharmacol.2. 199-203 (1995)
• [文献書誌] Ui, H.: "A novel cyclic lipoundecapeptide, pholipeptin, isolated from Pseudomonas Sp." Tetrahedron Lett.36. 7479-7480 (1995)
• [文献書誌] Sakai, T.: "Absolute configuration of spicamycin, an antitumor antibiotic produced by Streptomyces alanosinicus." J. Antibiotics. 48. 899-900 (1995)
• [文献書誌] Hayakawa, Y.: "Anguinomycins C and D, new antitumor antibiotics with selective cytotoxicity against transformed cells." J. Antibiotics. 48. 954-961 (1995)
• [文献書誌] Hayakawa, Y.: "Selective cytotoxicity of mycophenolic acid against transformed cells." J. Antibiotics. 48. 1182-1184 (1995)
• [文献書誌] Shin-ya, K.: "Novel neuronal cell protecting substances, aestivophoenins A and B, produced by Streptomyces purpeofuscus." J. Antibiotics. 48. 1378-1381 (1995)
• [文献書誌] Komiyama, K.: "Lousianins A, B, C and D : Non-steroidal growth inhibitors of testosterone SC 115 cells. I. Taxonomy, Fermentation, Isolation and Biological Characteristics." J. Antibiotics. 48. 1086-1089 (1995)
• [文献書誌] Takamatsu, S.: "Lousianins A, B, C and D : non-steroidal growth inhibitors of testosterone SC 115 cells. II. Physico-chemical properties and structural elucidation." J. Antibiotics. 48. 1090-1094 (1995)
• [文献書誌] Hayashi, M.: "Macrosphelide, a novel inhibitor of cell-cell adhesion molecule. I. Taxonomy, fermentation, isolation and biological activities." J. Antibiotics. 48. 1435-1439 (1995)
• [文献書誌] Takamatsu, S.: "Macrosphelide, a novel inhibitor of cell-cell adhesion molecule. II. Physicochemical properties and structure elucidation." J. Antibiotics. 49. 95-98 (1996)
• [文献書誌] Hayashi, M.: "Chlovalicin, a new cytocidal antibiotic produced by Sphorothrix sp. FO-4649. I. Taxonomy, fermentation, isolation and biological activities." J. Antibiotics. (in press).
• [文献書誌] Takamatsu, S.: "Chlovalicin, a new cytocidal antibiotic produced by Sphorothrix sp. FO-4649. II. Physicochemical properties and structural elucidation." J. Antibiotics. (in press).
• [文献書誌] Nakae, K.: "ERM, a PEA3 subfamily of Ets transcription factors, cancooperate with c-Jun." J. Biol. Chem.270. 23795-23800 (1995)
• [文献書誌] Nakajima, K.: "Signal transduction through IL-6 receptor : involvement of multiple protein kinases, Stat factors and a novel H-7-sensitive pathway." Ann. New York Acad. Sci.762. 55-70 (1995)
• [文献書誌] Hibi, M.: "IL-6 family cytokine and signal transduction : a model of the cytokine system." J. Mol. Med.(1996)
• [文献書誌] Kojima, H.: "IL-6-inducible complexes on an IL-6 response element of the junB promoter contain Stat3 and 36 kDa CRE-like site binding protein(s)." Oncogene. (in press).
• [文献書誌] Yamanaka, Y.: "Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation." EMBO J.(in press).
• [文献書誌] Yoneda, J.: "Role of the heparin-binding domain of chimeric peptides derived from fibronectin in cell spreading and motility." Exp. Cell Res.217. 169-179 (1995)
• [文献書誌] Sato, K.: "Inhibition of tumor-induced angiogenesis by a synthetic lipid A analogue with low toxicity, DT-5461." Jpn. J. Cancer Res.86. 374-382 (1995)
• [文献書誌] Fujii, H.: "Human melanoma invasion and metastasis enhancement by high expression of aminopeptidase N/CD13." Clin. Expl. Metastasis. 13. 337-344 (1995)
• [文献書誌] Sato, K.: "A novel synthetic lipid A analogue with low endotoxicity, DT-5461, prevents lethal endotoxemia." Infect. Immun.63. 2859-2866 (1995)
• [文献書誌] Mochizuki, M.: "Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20 (R)- and 20 (S)-ginsenoside-Rg3, of Red ginseng." Biol. Pharm. Bull.18. 1197-1202 (1995)
• [文献書誌] Komazawa, H.: "Combination of anti-cell adhesive synthetic Arg-Gly-Asp-Ser analogue and anti-cancer drugs heightens their original anti-metastatic activities." Oncology Res.7. 341-351 (1995)
• [文献書誌] Fujii, H.: "Antimetastatic activities of synthetic RGDS or RLDS peptide analogues and their inhibitory mechanisms." Biol. Pharm. Bull.18. 1681-1688 (1995)
• [文献書誌] Oikawa, T.: "Depudecin, a microbial metabolite containing two epoxide groups, exhibits anti-angiogenic activity in vivo." Chem. Pharm. Bull.18. 1305-1307 (1995)
• [文献書誌] Inaba, M.: "Reduced activity of anabolizing enzymes in 5-fluorouracil-resistant human stomach cancer cells." Jpn. J. Cancer Res.(in press).
• [文献書誌] Inaba, M.: "In vitro-in vivo correlation in anticancer drug sensitivity test using AUC-based concentrations and collagen gel droplet-embedded culture." Oncology. (in press).
• [文献書誌] Yano, S.: "Differential effects of anti-inflammatory cytokines (IL-4, IL-10 and IL-13) on tumoricidal and chemotactic properties of human monocytes induced by monocyte chemotactic and activating factor (MCAF)." J. Leukocyte Biol.57. 303-309 (1995)
• [文献書誌] Yano, S.: "Novel metastasis model of human lung cancer in NK-cell depleted SCID mice." Int. J. Cancer.(in press).
• [文献書誌] Fukuzawa,H: "Labeling of v-Src and BCR-ABL tyrosine kinases with [^<14>C]herbimycin A and its use in the elucidation of kinase inactivation mechanism." FEBS Letters. 340. 155-158 (1994)
• [文献書誌] Murakami,Y: "Conversion of epidermal growth factor (EGF) into a stimulatory ligand for A431-cell growth by herbimycin A by decreasing the level of expression of EGF receptor." Biochemical Journal. 301. 57-62 (1994)
• [文献書誌] Murakami,Y.: "Accelerated degradation of 160 kDa EGF receptor precursor by the tyrosine kinase inhibitor herbimycin A in the endoplasmic reticulum of A431 human epidermoid carcinoma cells.Biochem." Biochemical Journal. 301. 63-68 (1994)
• [文献書誌] Beaty,C.D.: "Lipopolysaccharide induced cytokine production in human monocytes:role of tyrosine phosphorylation in transmembrane signal transduction." European Journal of Immunology. 24. 1278-1284 (1994)
• [文献書誌] Kanbe,T.: "Use of transcriptional enhancer elements responsive to Ras,protein kinase A and protein kinase C to evaluate inhibitors of specific signal transduction pathways." Biological Pharmacentical Bulleti22GD05:17. 779-783 (1994)
• [文献書誌] Okabe,M.: "Effect of herbimycin A,and inhibitor of tyrosine kinase,on protein tyrosine kinase activity and phosphotyrosyl proteins of Ph^1-positive leukemia cells." Leukemia Research. 18. 213-220 (1994)
• [文献書誌] Okabe,M: "In vivo antiumor acitvity of herbimycin A,a tyrosine kinase inhibitor,targeted against BCR/ABL oncoprotein in mice bearing BCR/ABL transfected cells." Leukemia Research. 18. 867-873 (1994)
• [文献書誌] Higa,T.: "Establishment and characterization of a new Ph^1-positive ALL cell line (ALL/MIK)presenting bcr gene rearrangement on bcr-2 and LL-type transcript:Suggestion of in vitro differentiation to monocytoid lineage." Leukemic & Lyrphoma. 12. 287-296 (1994)
• [文献書誌] Kurosawa,M.: "p53 Gene mutation in the chronic phase was not detected in the myeloid crisis of a chronic myelocytic leukemia case." Blood. 83. 2750-2752 (1994)
• [文献書誌] Kunieda,Y.: "Chronic myeloid leukemia presenting ALL-type BCR/ABL transcript." Ann.Hematol.69. 189-193 (1994)
• [文献書誌] Okabe,M.: "Establishment and characterization of a new Ph1-positive chronic myeloid leukemia cell line MC3 with tri-lineage phenotype and an altered p53 gene." Leuk.Lymph.(in press).
• [文献書誌] Kunieda,Y.: "Effect of rhG-CSF on infection complications and impaired function of neutrophils secondary to chemotherapy for non-Hodgkin's lymphoma." Leuk.Lymph.(in press).
• [文献書誌] Kanbe,T.: "Phenotypic reversion induced by anthracyclines in ras oncogene-expressed calls;structure-activity relationships." Biol.Pharm.Bull.17. 527-530 (1994)
• [文献書誌] Tsuchiya,KS.: "Monoclonal antibody raised against apopretein of C-1027;effect on biochemical and biological activities of the holoantibiotic." J.Antibiotics. 47. 787-791 (1994)
• [文献書誌] Higashi,K.: "Daidzein inhibits insulin-or insulin-like growth factor-1-mediated signaling in cell cycle progression of Swiss 3T3 cell." Biochim.Biophys.Acta22GD15:1221. 29-35 (1994)
• [文献書誌] Ogawara,H.: "Inhibitors of diacylglycerol kinase from Drechslera sacchari." J.Antibiotics. 47. 499-501 (1994)
• [文献書誌] Ishigami,K.: "Cororubicin,a new anthracycline antibiotic generating active oxygen in tumor cells." J.Antibiotics. 47. 1219-1225 (1994)
• [文献書誌] Kamishohara,M.: "Antitumor activity of SPM VIII,a derivative of the nucleoside antibiotic spicamycin,against human tumor xenografts." J.Antibiotics. 47. 1305-1311 (1994)
• [文献書誌] Hayakawa,Y.: "Menoxymycins A and B,antitumor antibiotics generating active oxygen in tumor cells." J.Antibiotics. 47. 1344-1347 (1994)
• [文献書誌] Fujitani,Y.: "Transcriptional activation of the IL-6 response element in the junB promoter is mediated by multiple Stat family proteins." Biochem.Biophys.Res.Comnun.202. 1181-1187 (1994)
• [文献書誌] Takeda,T.: "E1A repression of IL-6-induced gene activation by blocking the assembly of IL-6 response element binding complexes." J.Immunol. 153. 4573-4582 (1994)
• [文献書誌] Nakajima,K.: "Interleukin 6 receptor-mediated signal transduction pathways." Gann Monograph on Cancer Res.42. 37-49 (1994)
• [文献書誌] Nakajima,K.: "Signal transduction through IL-6 receptor:Involvement of multiple protein kinase,Stat factors and a novel H7-sensitive pathway." Ann.Nwe York Acad.Sci.(in press).
• [文献書誌] Otani,N.: "Influence of growth factors on in vitro invasiveness and type IV collagenolysis of human renal cell carcinoma cells." J.Urol.151. 223-226 (1994)
• [文献書誌] Kobayashi,T.: "Cell-surface sulfoglycolipids are involved in the attachment of renal-cancer cells to laminin." Int.J.Cancer. 56. 281-285 (1994)
• [文献書誌] Yoo,Y,C.: "MDP-Lys(L18),a lipophilic derivative of muramyl dipeptide,inhibits the metastasis of haematogenous and nonhaematogenous tumours in mice." Vaccine. 12. 175-180 (1994)
• [文献書誌] Saiki,I.: "Influence of fibroblasts on the invasion and migration of highly or weakly metastatic B16 melanoma cells." Int,J.Cancer. 56. 867-873 (1994)
• [文献書誌] Saiki,I.: "Antiadhesion peptides in the prevention of tumour metastasis." Clin.Immuuother.1. 307-318 (1994)
• [文献書誌] Masumori,N.: "Inhibitory effect of minocycline on in vitro invasion and experimental metastasis of mouse renal adenocarcinoma." J.Urol. 151. 1400-1404 (1994)
• [文献書誌] Sato,K.: "Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng,ginsenoside-Rb2." Biol.Pharm.Bull.17. 635-639 (1994)
• [文献書誌] Yoneda,J.: "Inhibitory effect of recombinant fibronectin polypeptides inhibit adhesion of liver-metastatic lymphoma cells to hepatic sinusoidal endothelial cells followed by the tumor invasion." Jpn.J.Cancer Res.85. 723-734 (1994)
• [文献書誌] Yoneda,J.: "Role of the heparin-binding domain of chimeric peptides derived from fibronectin on the cell spreading and motility." Exp.Cell.Res.(in press)
• [文献書誌] Oikawa,T.: "Possible functional groups responsible for inhibition of in vivo angiogenesis by herbimycin A." Biol.Pharm.Bull. 17. 1430-1432 (1994)
• [文献書誌] Oikawa,T.: "Strategies to find novel angiogenesis inhibitors as potential therapeutic agents for cancer." Curr.Med.Chem.2. 406-417 (1994)
• [文献書誌] Oikawa,T.: "Three isoforms of platelet-derived growth factors all have the capability to induce angiogenesis in vivo." Biol.Pharm.Bull.(in press).
• [文献書誌] Inaba,M.: "Flow cytometric analysis of cell-killing actions of 5-fluorouracil in human colorectal cancer cells." Oncol.Res.6. 303-309 (1994)
• [文献書誌] Inaba,M.: "Different modes of cell-killing action between DNA topoisomerase I and II inhibitors revealed by kinetic analysis." Jpn.J.Caucer.Res. 85. 187-193 (1994)
• [文献書誌] Mizuno,K.: "Autonomous expressions of cytokine genes by human lung cancer cells and their paracrine regulation." Jpn.J.Cancer.Res.85. 179-186 (1994)
• [文献書誌] Yano,S.: "Cyclosporine A enhances susceptibility of multi-drug resistant human cancer cells to anti-P-glycoprotein antibody-dependent cytotoxicity of monocytes,but not of lymphocytes." Jpn.J.Cancer.Res.85. 194-203 (1994)
• [文献書誌] Sone,S.: "Production of IL-1 and its receptor antagonist is regulated differently by IFN-γ and IL-4 in human monocytes and alveolar macrophages." Enr.Respir.J.7. 657-663 (1994)
• [文献書誌] Sone,S.: "Local interleukin-2 therapy for cancer,and its effector induction mechanisms." Oncology. 51. 170-176 (1994)
• [文献書誌] Yano,S.: "Differential effects of anti-inflammatory cytokines(IL-4,IL-10 and IL-13) on tumoricidal and chemotactic properties of human monocytes induced by monocyte chemotactic and activating factor(MCAF)." J.Leukocyte Biol.(in press).
• [文献書誌] Numazawa,S.: "Involvement of Na^+,K^+-ATPase inhibition in K562 cell differentiation induced by bufalin." J.Cell.Physiol.160. 113-120 (1994)
• [文献書誌] Takii,T.: "Interleukin-1 down-regulates type I interleukin 1 receptor mRNA expression in a human fibroblast cell line TIG-1 in the absence of prostaglandin E_2 synthesis." Lymph.Cytok.Res.13. 213-219 (1994)
• [文献書誌] Minami,Y.: "Structure of cypemycin,a new peptide antibiotic." Tetrahed.Lett.35. 8001-8004 (1994)